Key Points• We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059.• ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/ refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a doselimiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. (Blood. 2016;127(4):411-419)

Previously, we have shown that humans with amblyopia exhibit deficits for global motion discrimination that cannot be simply ascribed to a reduction in visibility or contrast sensitivity. Deficits exist in the processing of global motion in the fronto-parallel plane that suggest reduced extra-striate function (i.e., MT) in amblyopia. Here, we ask whether such a deficit also exists for rotation and radial components of optic flow that are first processed at higher sites along the dorsal pathway (i.e., MSTd). We show that similar motion processing deficits occur in our amblyopic group as a whole for translation, rotation, and radial components of optic flow and that none of these can be solely accounted for by the reduced visibility of the stimuli. Furthermore, on a subject-by-subject basis there is no significant correlation between the motion deficits for radial and rotational motion and those for translation, consistent with independent deficits in dorsal pathway function up to and including MSTd.

This study compared the effects of age on the perception of translational, radial, and rotational global motion patterns. Motion coherence thresholds were measured for judging the direction of each motion type as a function of contrast (visibility) and temporal sampling rate in young and elderly participants. Coherence thresholds decreased as dot contrast increased asymptoting at high dot contrasts but were higher in elderly compared to young participants. This equated to global motion impairment in the elderly of a factor of around 2, characterized by a shift of the threshold vs. contrast function along the horizontal axes (dot contrast). The effect of contrast interacted with the temporal sampling rate. Old participants were deleteriously affected by reduced temporal sampling particularly at low contrasts. The findings suggest that age-related changes in global motion perception may be driven principally by deficits in contrast encoding, rather than by deficits in motion integration and suggest a role for increased internal noise in the older visual system.

This study investigates four key issues concerning the binocular properties of the mechanisms that encode global motion in human vision: (1) the extent of any binocular advantage; (2) the possible site of this binocular summation; (3) whether or not purely monocular inputs exist for global motion perception; (4) the extent of any dichoptic interaction. Global motion coherence thresholds were measured using random-dot-kinematograms as a function of the dot modulation depth (contrast) for translational, radial and circular flow fields. We found a marked binocular advantage of approximately 1.7, comparable for all three types of motion and the performance benefit was due to a contrast rather than a global motion enhancement. In addition, we found no evidence for any purely monocular influences on global motion detection. The results suggest that the site of binocular combination for global motion perception occurs prior to the extra-striate cortex where motion integration occurs. All cells involved are binocular and exhibit dichoptic interactions, suggesting the existence of a neural mechanism that involves more than just simple summation of the two monocular inputs.

Our novel findings demonstrate considerable retinal layer abnormalities in schizophrenia that are related to clinical features and visual function. With time, SD-OCT could provide easily-measurable biomarkers to facilitate clinical assessment and further our understanding of the disease.

Summary We report the results of a pilot study assessing the use of digital ‘virtual slides’ in haematological quality assessment. Conducted together with the UK National External Quality Assessment Scheme for General Haematology, the study involved 166 separate participants, using the format of a typical assessment exercise. The results revealed substantial concordance of observations made using digital slides with those reported in previous glass slide surveys that used identical cases. Participant feedback strongly supported the use of electronic slides in teaching and assessment roles. Our results suggest roles for this new electronic resource in external quality assessment (EQA), education and continuing professional development.

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The consequences of visual decline in aging have a fundamental and wide-reaching impact on age-related quality of life. It is of concern therefore that evidence suggests that normal aging is accompanied by impairments in the ability to effectively encode global motion. Global motion perception is a fundamentally important process. It enables us to determine the overall velocity of spatially-extensive objects in the world and provides us with information about our own body movements. Here, we review what is currently known about the effects of age on performance for encoding the global motion information available in random dot kinematograms (RDKs), a class of stimuli widely used to probe the mechanisms underlying motion perception. We conclude that age-related deficits in global motion perception are not all encompassing. Rather, they appear to be specific to certain stimulus conditions. We also examine evidence for an interaction between age and gender and consider the efficacy of techniques such as visual perceptual learning that may attenuate some of the visual deficits in the older adult population.